Project Summary/Abstract: The number of individuals aged 65 years and older is rapidly increasing in the United States, projected to account for over 20% of the population by 2030. In this older population, unexplained exercise intolerance and dyspnea (breathlessness) with exertion is common and negatively affects qualify of life. It is possible that aging of the pulmonary vasculature exerts an unrecognized influence on exercise capacity and symptoms in older individuals. Accordingly, we hypothesize that the pulmonary vasculature will exhibit significant changes in alveolar-capillary recruitment, vascular pressures, and nitric oxide (NO)-mediated smooth muscle relaxation in older vs. younger individuals, particularly during exercise. It is well-known that aging is associated with a stiffening of the pulmonary vasculature (due to vascular wall remodeling), and it is possible that smooth muscle changes also play a role. Stiffening of the pulmonary vasculature leads to an increased resistance to blood flow throughout the lungs and a subsequent increase in pulmonary vascular pressures. Additionally, the aging lungs demonstrate enlarged alveoli and a decrease in the number of pulmonary capillaries, leading to a deterioration of the air-blood interface responsible for gas exchange. This worsened ability of gases to transfer from the alveoli to pulmonary-capillary blood results in a decreased lung diffusing capacity, a consequence of both decreased alveolar-membrane surface area and pulmonary-capillary blood volume. During exercise in a healthy individual, blood flow to the lungs is increased through both distension of perfused capillaries and recruitment of under-perfused capillaries. However, the effects of aging on the pulmonary vasculature likely alter the ability to increase alveolar-membrane surface area and pulmonary-capillary blood volume. These effects are likely exacerbated by a decreased cardiac output during exercise in older individuals. Indeed, preliminary studies in our laboratory suggest that the mechanism responsible for an increased lung diffusing capacity during exercise differs between young and old individuals. We hypothesize that these differences are a function of changes in the pulmonary vasculature leading to a mismatch between the rise in cardiac output (forward flow) and the rise in pulmonary arterial pressure during exercise in older individuals. Therefore, the objectives of the proposed studies are to 1) optimize a novel method for quantifying alveolar-capillary recruitment during exercise, 2) determine how changes in pulmonary vascular pressures at a given blood flow affect alveolar-capillary recruitment during exercise with aging, and 3) determine if alterations in smooth muscle function contribute to altered alveolar-capillary recruitment with aging via administration of pulmonary vasodilators during exercise. These studies will lead to a detailed understanding of changes to the pulmonary vasculature with aging, such that future studies may investigate novel treatment targets in older individuals experiencing unexplained exercise intolerance and dyspnea.